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Peer-reviewedCC BY-NC-ND 4.0Immunology

MyD88‐Family Adaptors: Compartmentalised Signalling and Non‐Immune Functions

  • Seshu Vardhan Pothabathula1,2,3
  • Saurabh Mishra1,2,3
  • Pugazhendhi Kannan1,2,3
  • Annette Bellar1,2,3
  • Amy Attaway1,2,3
  • Nicole Welch1,2,3
  • Srinivasan Dasarathy1,2,3
  1. 1Department of Inflammation and Immunity Lerner Research Institute, Cleveland Clinic Cleveland Ohio USA
  2. 2Department of Gastroenterology and Hepatology Lerner Research Institute, Cleveland Clinic Cleveland Ohio USA
  3. 3Department of Pulmonary Medicine Cleveland Clinic Cleveland Ohio USA
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Abstract

The myeloid differentiation primary response protein 88 (MyD88) family of Toll/interleukin‐1 receptor (TIR) domain‐containing adaptor proteins constitutes a central signalling hub that integrates innate immune sensing with tissue‐specific stress responses. This family comprises five mammalian members: MyD88, TIRAP/MAL, TRIF/TICAM‐1, TRAM/TICAM‐2 and SARM1 (also known as MyD88‐1 through MyD88‐5). While these adaptors are classically defined by their roles in immune and haematopoietic cells, accumulating genetic and mechanistic evidence demonstrates critical, cell‐intrinsic functions in non‐immune tissues. Canonical MyD88 signalling assembles IRAK‐containing complexes to activate NF‐κB and MAPK pathways, whereas TIRAP and TRAM function as sorting adaptors that impose spatial and receptor specificity. TRIF mediates MyD88‐independent interferon programs downstream of Toll‐like receptor (TLR)‐3 and internalised TLR‐4. Beyond immunity, MyD88‐family signalling regulates epithelial barrier integrity, hepatic metabolic homeostasis, skeletal muscle metabolism and atrophy, endothelial permeability, renal injury responses and neuronal degeneration. Notably, SARM1 represents a functionally divergent family member whose TIR domain acts as an intrinsic NAD+ hydrolase driving axonal degeneration. Here, we synthesise structural, genetic and cell‐specific studies to highlight how compartmentalised adaptor usage and domain‐specific mechanisms generate context‐dependent signalling outcomes across immune and non‐immune tissues. These insights redefine MyD88‐family adaptors as modular regulators of tissue physiology and disease, with implications for targeted therapeutic intervention.

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Cite

BibTeXRIS
BibTeX
@article{pothabathula2026myd88family,
  title = {{MyD88‐Family Adaptors: Compartmentalised Signalling and Non‐Immune Functions}},
  author = {Seshu Vardhan Pothabathula and Saurabh Mishra and Pugazhendhi Kannan and Annette Bellar and Amy Attaway and Nicole Welch and Srinivasan Dasarathy},
  journal = {Immunology},
  year = {2026},
  month = aug,
  doi = {10.1111/imm.70184},
  url = {https://doi.org/10.1111/imm.70184},
  note = {CC BY-NC-ND 4.0},
}
RIS
TY  - JOUR
TI  - MyD88‐Family Adaptors: Compartmentalised Signalling and Non‐Immune Functions
AU  - Seshu Vardhan Pothabathula
AU  - Saurabh Mishra
AU  - Pugazhendhi Kannan
AU  - Annette Bellar
AU  - Amy Attaway
AU  - Nicole Welch
AU  - Srinivasan Dasarathy
PY  - 2026
DA  - 2026/08/04
JO  - Immunology
DO  - 10.1111/imm.70184
UR  - https://doi.org/10.1111/imm.70184
AB  - The myeloid differentiation primary response protein 88 (MyD88) family of Toll/interleukin‐1 receptor (TIR) domain‐containing adaptor proteins constitutes a central signalling hub that integrates innate immune sensing with tissue‐specific stress responses. This family comprises five mammalian members: MyD88, TIRAP/MAL, TRIF/TICAM‐1, TRAM/TICAM‐2 and SARM1 (also known as MyD88‐1 through MyD88‐5). While these adaptors are classically defined by their roles in immune and haematopoietic cells, accumulating genetic and mechanistic evidence demonstrates critical, cell‐intrinsic functions in non‐immune tissues. Canonical MyD88 signalling assembles IRAK‐containing complexes to activate NF‐κB and MAPK pathways, whereas TIRAP and TRAM function as sorting adaptors that impose spatial and receptor specificity. TRIF mediates MyD88‐independent interferon programs downstream of Toll‐like receptor (TLR)‐3 and internalised TLR‐4. Beyond immunity, MyD88‐family signalling regulates epithelial barrier integrity, hepatic metabolic homeostasis, skeletal muscle metabolism and atrophy, endothelial permeability, renal injury responses and neuronal degeneration. Notably, SARM1 represents a functionally divergent family member whose TIR domain acts as an intrinsic NAD+ hydrolase driving axonal degeneration. Here, we synthesise structural, genetic and cell‐specific studies to highlight how compartmentalised adaptor usage and domain‐specific mechanisms generate context‐dependent signalling outcomes across immune and non‐immune tissues. These insights redefine MyD88‐family adaptors as modular regulators of tissue physiology and disease, with implications for targeted therapeutic intervention.
SN  - 0019-2805
SN  - 1365-2567
ER  -